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Comparative Outcomes of Ampicillin-Sulbactam versus Cefazolin for Methicillin- Susceptible Staphylococcus aureus Infective Endocarditis: A Multicentre Cohort Study

This multicentre retrospective cohort study found that ampicillin-sulbactam and cefazolin yielded similar major clinical outcomes for methicillin-susceptible *Staphylococcus aureus* infective endocarditis, suggesting ampicillin-sulbactam is a viable alternative when standard antistaphylococcal agents are unavailable.

Original authors: Seniha Başaran, Derya Seyman, Serpil Özkan-Özturk, Nuran Sarı, Elif Mukime Sarıcaoğlu, Elif Tükenmez Tigen, Özlem Azap, Serap Şimşek Yavuz

Published 2026-07-09

📖 4 min read☕ Coffee break read

CC BY 4.0

Original authors: Seniha Başaran, Derya Seyman, Serpil Özkan-Özturk, Nuran Sarı, Elif Mukime Sarıcaoğlu, Elif Tükenmez Tigen, Özlem Azap, Serap Şimşek Yavuz

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine the human heart as a high-security fortress. Sometimes, a very tough invader called Staphylococcus aureus (specifically the "methicillin-susceptible" or MSSA variety) manages to sneak in and set up camp on the heart valves. This is called Infective Endocarditis. It's a serious infection that needs to be cleared out quickly and completely.

Usually, doctors have a "Gold Standard" weapon to fight this invader: a specific type of penicillin. However, in some places (like Turkey, where this study took place), that specific penicillin isn't available. So, doctors have to choose between two other weapons: Cefazolin (a common, trusted alternative) and Ampicillin-Sulbactam (a different combination drug often used for other infections).

The big question was: If the Gold Standard is missing, is Ampicillin-Sulbactam a good backup plan, or is it weaker than Cefazolin?

Here is what the researchers found, broken down simply:

The Experiment

The researchers looked back at medical records from 2014 to 2023 across 19 different hospitals. They found 89 patients who had this specific heart infection.

Group A (67 people): Treated mostly with Cefazolin.
Group B (22 people): Treated mostly with Ampicillin-Sulbactam.

They wanted to see who survived the hospital stay and who was still alive one year later.

The Results: A Tale of Two Numbers

When they first looked at the raw numbers, it seemed like the Ampicillin-Sulbactam group did surprisingly well.

In the hospital: Both groups had similar survival rates.
One year later: The group treated with Ampicillin-Sulbactam actually had a lower death rate (20%) compared to the Cefazolin group (47.5%).

However, this is where the story gets interesting.

The researchers realized that the two groups weren't exactly the same at the start. The Ampicillin-Sulbactam group had more patients with infections on the right side of the heart (which is generally easier to treat and has better survival rates naturally). They also had fewer patients with other serious health problems like kidney disease or diabetes.

When the researchers used a "statistical filter" to level the playing field—making sure they were comparing apples to apples rather than apples to oranges—the advantage of Ampicillin-Sulbactam disappeared.

The Final Verdict:
Once they accounted for the differences in patient health and infection location, there was no significant difference between the two drugs. Both drugs performed about the same.

What Actually Mattered for Survival?

The study found that the choice of drug wasn't the main factor deciding who lived or died. Instead, two other things were the real heroes and villains:

The Villain (Comorbidities): Patients who already had other serious health issues (like kidney disease or diabetes) were much more likely to pass away, regardless of which drug they got. It's like trying to win a race when you are already carrying a heavy backpack; the drug choice matters less than the weight you're already carrying.
The Hero (Heart Surgery): Patients who underwent surgery to fix or replace the infected heart valve were much more likely to survive. This suggests that physically removing the infected "fortress" is often more important than just the medicine used to kill the bacteria.

The Bottom Line

The researchers concluded that Ampicillin-Sulbactam is a reasonable backup plan if the standard penicillin isn't available. It didn't kill patients, and it didn't perform worse than Cefazolin when you look at the full picture.

They also noted that while Ampicillin-Sulbactam can sometimes struggle against high numbers of bacteria (a concept called the "inoculum effect"), in this real-world scenario, it seemed to work just fine, possibly because patients were also getting other antibiotics early on that lowered the bacterial load before the main treatment started.

In short: If you can't get the Gold Standard, Cefazolin is great, but Ampicillin-Sulbactam is a solid "Plan B" that gets the job done just as well in this specific heart infection scenario. The most important things for a patient's survival are their overall health and getting surgery if needed, not just which of these two specific drugs they receive.

Technical Summary: Comparative Outcomes of Ampicillin-Sulbactam versus Cefazolin for MSSA Infective Endocarditis

Problem Statement
Methicillin-susceptible Staphylococcus aureus (MSSA) is the leading cause of infective endocarditis (IE), accounting for approximately 70% of MSSA cases. Current international and national guidelines recommend antistaphylococcal penicillins (ASPs) or cefazolin as first-line therapies. However, ASPs are unavailable in certain regions, including Türkiye, necessitating the use of alternative $\beta$ -lactams. While cefazolin is widely accepted as an alternative, concerns exist regarding its susceptibility to the "inoculum effect" (reduced activity at high bacterial burdens), a phenomenon also observed with ampicillin-sulbactam in experimental studies. Despite the frequent clinical use of ampicillin-sulbactam for MSSA bacteremia and IE in Türkiye, there is a lack of clinical data evaluating its specific effectiveness in MSSA IE compared to cefazolin. Consequently, its role as a therapeutic alternative remains uncertain and is not currently supported by major guidelines.

Methodology
This study was a multicentre, retrospective cohort analysis based on the prospectively established Türkiye Endocarditis Group (TEG) registry.

Population: The study included 89 adult patients with definite MSSA IE diagnosed between 2014 and 2023.
Inclusion Criteria: Patients received either cefazolin or ampicillin-sulbactam as definitive therapy for at least 75% of the treatment course.
Exclusion Criteria: Patients receiving alternative definitive regimens, combination therapy with other anti-staphylococcal agents, those who died within the first 72 hours, or those transferred before treatment completion were excluded.
Groups: Patients were categorized into a cefazolin group ( $n=67$ ) and an ampicillin-sulbactam group ( $n=22$ ).
Endpoints: The primary outcome was all-cause in-hospital mortality. Secondary outcomes included recurrence of IE and one-year all-cause mortality.
Statistical Analysis: Univariate analyses were performed to identify risk factors, followed by a backward stepwise multivariable logistic regression model to identify independent predictors of one-year mortality, adjusting for potential confounders such as comorbidities and cardiac surgery.

Key Contributions
To the authors' knowledge, this is the first study specifically comparing ampicillin-sulbactam and cefazolin as definitive treatment options for MSSA IE. The study provides real-world evidence from multiple centres in Türkiye, a setting where standard antistaphylococcal agents are unavailable, addressing a gap in clinical data regarding ampicillin-sulbactam in severe MSSA infections.

Results

Baseline Characteristics: The two groups were generally comparable in demographics, comorbidities, and disease severity. However, right-sided IE was more frequent in the ampicillin-sulbactam group.
In-Hospital Mortality: No statistically significant difference was observed between the groups (22.4% for cefazolin vs. 4.5% for ampicillin-sulbactam; $p=0.105$ ).
Recurrence: No significant differences were found between the groups.
One-Year Mortality: In univariate analysis, one-year all-cause mortality was significantly lower in the ampicillin-sulbactam group compared to the cefazolin group (20.0% vs. 47.5%; $p=0.037$ ).
Multivariable Analysis: After adjusting for confounders, the association between ampicillin-sulbactam and lower one-year mortality was not statistically significant (OR 0.27, 95% CI 0.07–1.02, $p=0.053$ ).
Independent Predictors:
- Increased Mortality: The presence of comorbidities was independently associated with increased one-year mortality (OR 4.38, 95% CI 1.08–17.78, $p=0.039$ ).
- Improved Survival: Cardiac surgery (valve repair or replacement) was independently associated with improved survival (OR 0.25, 95% CI 0.08–0.81, $p=0.020$ ).

Significance and Claims
The authors conclude that ampicillin-sulbactam and cefazolin are associated with similar major clinical outcomes in MSSA IE when analyzed with appropriate adjustments. While univariate data suggested a survival benefit for ampicillin-sulbactam, this did not hold after multivariable adjustment.

The paper posits that ampicillin-sulbactam may represent a reasonable alternative treatment option for MSSA IE, particularly in settings where standard antistaphylococcal agents are unavailable. The authors suggest that the lack of significant difference in outcomes, despite theoretical concerns about the inoculum effect, may be explained by the use of high-dose ampicillin-sulbactam in Türkiye (up to 12 g/day), which could overcome the inoculum effect, or by the reduction of bacterial burden via empirical combination therapy prior to definitive treatment.

The study emphasizes that patient characteristics (specifically comorbidities) and the adequacy of source control (cardiac surgery) appear to exert a greater influence on long-term outcomes than the specific choice of $\beta$ -lactam agent. The authors acknowledge limitations, including the retrospective design, small sample size in the ampicillin-sulbactam group, and the lack of systematic microbiological evaluation. They state that larger prospective studies incorporating microbiological and pharmacodynamic assessments are warranted to further clarify the role of ampicillin-sulbactam in this setting.

The Experiment

The Results: A Tale of Two Numbers

What Actually Mattered for Survival?

The Bottom Line

Technical Summary: Comparative Outcomes of Ampicillin-Sulbactam versus Cefazolin for MSSA Infective Endocarditis

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